Patients were initially treated with radiation only, usually split course

Dose-escalation in RTOG 73-01 established 60 Gy in 2 Gy/fx as the standard regimen

Median survival was ~10 months, with 3-year survival <10%

Hyperfractionated RT alone did not show any beneft

Continuous Hyperfractionated Accelerated RadioTherapy (CHART) showed a significant improvement in OS. However, logistics of delivering RT TID x12 days straight, combined with OS improvement with chemotherapy have limited its adoption

CALGB, RTOG, and UK studies in mid-1990's established induction chemo + RT superior for median OS, although absolute benefit was not large (2-4 months). There was a significantly higher proportion of long term survivors. There was no impact on local progression, but distal failure was significantly less

Hyperfractionated RT after chemo induction did not show any benefit over standard RT

Induction chemo alone, without RT, was comparable in median OS, but inferior in long term survivors compared to induction chemo + RT. RT was considered a necessary component of treatment

At the same time, concurrent chemotherapy and RT were evaluated. The only survival benefit of concurrent chemo-RT over RT alone was in an EORTC trial, which used split-course RT with a 3 week rest. The other 3 trials with standard RT fractions were negative. The chemo used was a single agent.

Small overall chemo benefit was demonstrated in a meta-analysis setting in 1995, and confirmed to be 4% absolute benefit at 2 years in a subsequent meta-analysis. Essentially any two agents are superior to any single agent; adding a third drug did not provide additional benefit

However, the timing of giving chemotherapy and RT was unclear. Both induction and concurrent chemo appear to provide survival benefit, induction chemo via improved distal control and concurrent chemo via improved local control.

Direct comparisons in several randomized trials established concurrent chemo-RT as the superior regimen, at the cost of increased in-field toxicity (especially esophagitis)

There is no benefit to induction chemotherapy, followed by concurrent chemo-RT (CALGB B39801, LAMP). The later RT starts, the worse the outcomes

The role of consolidative chemo after concurrent chemo-RT is under evaluation

The role of elective nodal irradiation is also evolving, with single institution series suggesting minimal benefit, and one randomized trial (China) finding that dose escalation to 68-74 Gy due to lower volume treated resulted in improved overall survival

The current standard of care can be considered concurrent chemo with 2 agents containing platinum, and thoracic RT to 60 Gy in QD fractions.

319 pts, locally advanced, unresectable. Randomized to 1) Vindesine weekly, 2) RT to 60 Gy (2 Gy/fx), or 3) Vindesine + RT. Vindesine was given weekly for 6 weeks then every other week. Cross over to the other arm was done for disease progression.

Comment: Low survival compared to other trials, possibly due to lower chemo dose due to using carboplatin and not cisplatin.

Locally Advanced Multimodality Protocol (LAMP), 2005 (1998-2001) - Randomized Phase II. Closed early due to nonaccrual. Opened before concurrent chemo-RT was established as standard, with Arm 1 sequential chemo-RT as control. Arm 2 was closed early at interim analysis. Eventually interest in Arm 1 slowed down, and trial was closed. Results compared to historical RTOG 88-08

Arm 3: Concurrent chemo/RT followed by consolidative chemotherapy. Concurrent chemo/RT (as in Arm 2) followed by two cycles of chemotherapy (as in Arms 1&2) 3-4 weeks after completion of concurrent therapy.

Retrospective. 524 patients, definitive IFRT. Only LN+ by biopsy or >=1.5 cm short axis by CT included in CTV. Elective nodal failure (ENF) defined as recurrence in initially LN- in absence of local failure. Median F/U 3.4 years

Outcome: ENF in 6%; 2-year elective nodal control 92%, local control 51%; median time to nodal failure 6 months

Toxicity: Myelosuppression, alopecia, and fatigue more frequent in cisplatin/docetaxel group, but skin toxicity, liver dysfunction, and diarrhoea more frequent in the gefitinib group. Two patients (2%) developed interstitial lung disease

Conclusion: Patients with EGFR mutations have longer PFS on gefitinib than on cisplatin/docetaxel

Outcome: On multivariate analysis, only baseline global QoL score was prognostic for survival; no other variables were significant. Patients with QoL score <67 (median value) had 70% higher rate of death (SS); 10-point increase in QoL corresponded to 10% decrease in hazard of death. Both physical functioning (QLQ-30) and dyspnea (LC-13) were independently predictive for OS on univariate analysis

Conclusion: Quality of life score replaced all known prognostic factors as sole predictor for long-term survival